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Age- and sex-related reference values for serum adhesion molecule concentrations in healthy individuals: intercellular adhesion molecule-1 and E-, P-, and L-selectin.

Intercellular adhesion molecule-1 (ICAM-1) and E-, P-, and L-selectin are cellular adhesion molecules involved in the recruitment of leukocytes on the activated vessel wall during inflammation (1) and play an important role in the early stages of atherosclerosis and its complications (2). Thus, the measurement of soluble adhesion molecules in serum may have diagnostic relevance in many inflammatory diseases (3). A profile of soluble adhesion molecule concentrations may allow better therapeutic decisions in inflammatory and autoimmune disorders, infection, cancer, and cardiovascular pathologies and may also aid in the prediction of cardiovascular events (4,5). However, the use of these markers in clinical practice depends critically on knowledge of their reference values.

The purpose of the present study was to establish age-and sex-specific reference intervals for serum concentrations of soluble ICAM-1 and E-, P-, and L-selectin in healthy children (4-17 years) and adults (18-55 years).

Blood samples were taken from healthy individuals (157 boys and 146 girls 4-17 years of age and 245 men and 250 women 18-55 years of age) who were members of the Stanislas cohort (6). Participants were of French origin (Vosges and Meurthe et Moselle); free from serious and/or chronic illnesses, especially cardiovascular, hepatic, or renal diseases; and were not on treatment with lipid-lowering drugs. Volunteers with aspartate amino-transferase, alanine aminotransferase, or [gamma]-glutamyl-transferase activities >200 U/L, apolipoprotein E concentrations >200 mg/L, orosomucoid or haptoglobin concentrations >3 g/L, cholesterol or triglyceride concentrations >10 mmol/L, C-reactive protein concentrations >30 mg/L, or glucose concentrations >8 mmol/L were excluded. The study was approved by the local ethics committee of Nancy (France), and each participant gave written informed consent.

Venous blood samples were collected by venipuncture after an overnight fast (7) and centrifuged (1500g for 15 min at 4[degrees]C) within 2 h after collection. Serum samples obtained were immediately frozen at -196[degrees]C in liquid nitrogen until analysis (storage period, 21-39 weeks; mean, 31 weeks).

ICAM-1 and E-, P-, and L-selectin concentrations were measured with commercially available ELISAs (R&D System). The intra- and interassay CVs for the adhesion molecules were as follows: ICAM-1, 6.6% and 8.6%; E-selectin, 9.4% and 15%; P-selectin, 5.8% and 7.0%, and L-selectin, 8.9% and 12%.

Statistical analyses were performed with SAS software, Ver. 8.01 (SAS Institute Inc.). Because the distribution of serum concentrations of ICAM-1 and E-, P-, and L-selectin were skewed, [log.sub.10] transformations were applied. ANOVA and pairwise comparison procedures with Bonferroni correction were performed to test differences in soluble ICAM-1 and E-, P-, and L-selectin concentrations between age and sex groups. Reference values were estimated using a nonparametric method (5th and 95th percentiles).

Relationships between the length of time of storage at -196[degrees]C and the concentrations of the four adhesion molecules were examined, as recommended by Demerath et al. (8). We found no significant effect of storage length; we therefore did not adjust analyte values for this factor.

The mean (SD), median, and 5th and 95th percentile concentrations of the four adhesion molecule for three groups of children (4-9,10-14, and 15-17 years) and three groups of adults (18-34, 35-44, and 45-55 years) are presented in Table 1.

From 4 to 17 years, log-transformed ICAM-1 and E-, P-, and L-selectin concentrations significantly decreased in both boys and girls. The P values for the differences in the concentrations of ICAM-1 and E-, P-, and L-selectin across the three age groups were [less than or equal to] 0.001, [less than or equal to] 0.001, [less than or equal to] 0.05, and [less than or equal to] 0.001, respectively (ANOVA tests). No significant sex-related differences were detected in children. From 18 to 55 years, L-selectin concentrations decreased with age in both sexes (P [less than or equal to] 0.001), whereas E-selectin concentrations increased only in women (P [less than or equal to] 0.05). ICAM-1 and P-selectin concentrations did not vary significantly across the three age groups, independent of gender. ICAM-1, E-selectin, and P-selectin concentrations were significantly higher in men than in women (P [less than or equal to] 0.05, [less than or equal to] 0.001 and [less than or equal to] 0.001, respectively, t-test), whereas no significant sex effect was observed for L-selectin concentrations.

Circulating soluble isoforms of adhesion molecules in blood result either from the release of membrane-bound molecules by proteolytic cleavage of the extracellular portion (ICAM-1 and E-, P-, and L-selectin) or from alternative splicing of the mRNA lacking the transmembrane domain (P-selectin) (3). The concentrations of these soluble isoforms presumably reflect their relative abundance as membrane-bound molecules. The key role played by these molecules in the recruitment of leukocytes by the endothelium suggests that measurement of their circulating concentrations may be useful for monitoring the process of inflammation of the vessel wall. The measurement of adhesion molecule concentrations is thus of clinical interest. The ready availability of commercial ELISAs for determination of soluble adhesion molecules has greatly facilitated research in the clinical significance of their concentrations. Higher concentrations have been reported in various inflammation-related diseases, mainly immune disorders, inflammation, cancer, and cardiovascular disease (3). Such high concentrations of circulating adhesion molecules may be of interest for diagnostic and prognostic purposes, as demonstrated for ICAM-1 and P-selectin, which provide useful information in healthy individuals and in patients with cardiovascular diseases (9). However, reference values for healthy children and adults have not been defined.

In the current study, we measured serum ICAM-1 and E-, P-, and L-selectin concentrations and determined their age and sex-specific reference intervals over a wide age range (4-55 years) in a healthy population of both sexes.

Earlier studies dealing with serum adhesion molecule (ICAM-1 and E-selectin) concentrations in healthy pediatric populations pointed to an age dependency (10-12). In this study, we observed that mean serum ICAM-1 and E-, P-, and L-selectin concentrations steadily decrease during childhood. ICAM-1 and P-selectin concentrations did not vary with age in adulthood, whereas L-selectin decreased in both sexes and E-selectin increased in women only. Although the decrease in adhesion molecule concentrations with age in children has already been described, its physiologic significance during normal development is unknown. Authors of previous studies in adults observed that ICAM-1, E-selectin, and P-selectin concentrations did not vary with age between 18 and 65 years (3, 5, 8,10,13,14), but the decrease in L-selectin during adulthood has not been described.

ICAM-1, E-selectin, and P-selectin concentrations display a significant sex dependency only in adults, with men having higher concentrations than women. These sex-related differences, as reported previously in healthy adults (8,14-16), are probably partly attributable to steroid hormones, especially estrogen. Indeed, healthy postmenopausal women on hormone replacement therapy had lower concentrations of these adhesion molecules than controls not on replacement therapy (7,17,18), and in vitro studies have shown negative regulation of adhesion molecule expression by estrogen (19).

In conclusion, we have shown that serum ICAM-1 and E-, P-, and L-selectin concentrations are age-dependent in childhood and sex-dependent in adulthood. Application of age- and sex-adjusted reference intervals appears to be necessary. These findings emphasize the need to use age(for children) and sex-matched controls (for adults) in all analyses of the possible clinical impact of circulating concentrations of adhesion molecules.

We thanks Prof. G. Siest, Dr. C. Sass, and the Centre de Medecine Preventive of Vandoeuvre-les-Nancy, France, for management of the Stanislas cohort. This work was supported by an IDS grant (INSERM no. 4DOOSE/1999). Anne Ponthieux has received a grant from Societe Francaise d'Hypertension Arterielle.

References

(1.) Springer TA. Traffic signals for lymphocyte recirculation and leukocyte emigration: the multistep paradigm. Cell 1994;76:301-14.

(2.) Huo Y, Ley K. Adhesion molecules and atherogenesis. Acta Physiol Scand 2001;173:35-43.

(3.) Gearing AJ, Newman W. Circulating adhesion molecules in disease. Immunol Today 1993;14:506-12.

(4.) Ricker PM, Buring JE, Rifai N. Soluble P-selectin and the risk of future cardiovascular events. Circulation 2001;103:491-5.

(5.) Hwang SJ, Ballantyne CM, Sharrett AR, Smith LC, Davis CE, Gotto AM Jr, et al. Circulating adhesion molecules VCAM-1, ICAM-1, and E-selectin in carotid atherosclerosis and incident coronary heart disease cases: the Atherosclerosis Risk In Communities (ARIC) study. Circulation 1997;96:4219-25.

(6.) Siest G, Visvikis S, Herbeth B, Gueguen R, Vincent-Viry M, Sass C, et al. Objectives, design and recruitment of a familial and longitudinal cohort for studying gene-environment interactions in the field of cardiovascular risk: the Stanislas Cohort. Clin Chem Lab Med 1998;36:35-42.

(7.) Osterud B, Elvevoll EO, Brox J, Anderssen T, Eliassen LT, Halvorsen H, et al. Haemostatic parameters related to lipids and adhesion molecules. Blood Coagul Fibrinolysis 1999;10:465-70.

(8.) Demerath E, Towne B, Blangero J, Siervogel RM. The relationship of soluble ICAM-1, VCAM-1, P-selectin and E-selectin to cardiovascular disease risk factors in healthy men and women. Ann Hum Biol 2001;28:664-78.

(9.) Blankenberg S, Barbaux S, Tiret L. Adhesion molecules and atherosclerosis. Atherosclerosis 2003;in press.

(10.) Andrys C, Pozler O, Krejsek J, Derner V, Drahosova M, Kopecky O. Serum soluble adhesion molecules (sICAM-1, sVCAM-1 and sE-selectin) in healthy school aged children and adults. Acta Medica 2000;43:103-6.

(11.) Nash MC, Wade AM, Shah V, Dillon MJ. Normal levels of soluble E-selectin, soluble intercellular adhesion molecule-1 (sICAM-1), and soluble vascular cell adhesion molecule-1 (sVCAM-1) decrease with age. Clin Exp Immunol 1996;103:167-70.

(12.) Sack U, Burkhardt U, Borte M, Schadlich H, Berg K, Emmrich F. Age-dependent levels of select immunological mediators in sera of healthy children. Clin Diagn Lab Immunol 1998;5:28-32.

(13.) Rudloff S, Thomas C, Kunz C. Variations of soluble intercellular cell adhesion molecule 1 (sICAM-1) in serum of adult volunteers. Eur J Med Res 1995;1:171-2.

(14.) Blann AD, Daly RJ, Amiral J. The influence of age, gender and ABO blood group on soluble endothelial cell markers and adhesion molecules. Br J Haematol 1996;92:498-500.

(15.) Barbaux SC, Blankenberg S, Rupprecht HJ, Francomme C, Bickel C, Hafner G, et al. Association between P-selectin gene polymorphisms and soluble P-selectin levels and their relation to coronary artery disease. Arterioscler Thromb Vasc Biol 2001;21:1668-73.

(16.) Oger E, Alhenc-Gelas M, Plu-Bureau G, Mennen L, Cambillau M, Guize L, et al. Association of circulating cellular adhesion molecules with menopausal status and hormone replacement therapy. Time-dependent change in transdermal, but not oral estrogen users. Thromb Res 2001;101:35-43.

(17.) Koh KK, Bui MN, Mincemoyer R, Cannon RO III. Effects of hormone therapy on inflammatory cell adhesion molecules in postmenopausal healthy women. Am J Cardiol 1997;80:1505-7.

(18.) Koh KK, Jin DK, Yang SH, Lee SK, Hwang HY, Kang MH, et al. Vascular effects of synthetic or natural progestagen combined with conjugated equine estrogen in healthy postmenopausal women. Circulation 2001;103: 1961-6.

(19.) Caulin-Glaser T, Watson CA, Pardi R, Bender JR. Effects of 17/3-estradiol on cytokine-induced endothelial cell adhesion molecule expression. J Clin Invest 1996;98:36-42.

Anne Ponthieux, Bernard Herbeth, Suzanne Droesch, Daniel Lambert, and Sophie Visvikis * [Institut National de la Sante et de la Recherche Medicale (INSERM) U 525, 30 rue Lionnois, 54000 Nancy, France, and Centre de Medecine Preventive, 2 rue du Doyen Jacques Parisot, 54500 Vandoeuvre-les-Nancy, France; * address correspondence to this author at: INSERM Unite 525, 30 rue Lionnois, 54000 Nancy, France; fax 33-03-83-32-13-22, email Sophie.visvikis@cmp.u-nancy.fr]
Table 1. Mean, median, and age-specific reference intervals based
on the 5th and 95th percentiles for ICAM-1 and E-, P-, and L-selectin
concentrations in serum.

 ICAM-1, mg/L

 Mean
 n (SD) Median RI (a)

Males
 4-9 years 12 317 (57) 300 251-437
 10-14 years 59 295 (62) 299 208-387
 5-17 years 86 268 (63) 261 192-354
 18-34 years 70 259 (69) 258 176-363
 35-44 years 92 269 (65) 262 181-379
 45-55 years 83 262 (64) 263 152-362

Females
 4-9 years 11 323 (54) 319 242-410
 10-14 years 64 287 (53) 279 221-389
 15-17 years 71 258 (55) 261 155-344
 18-34 years 73 251 (62) 241 165-374
 35-44 years 122 250 (62) 251 152-338
 45-55 years 55 245 (53) 242 168-337

 E-Selectin, mg/L

 Mean
 (SD) Median RI

Males
 4-9 years 72.5 (25.6) 70.7 30.5-111.7
 10-14 years 71.1 (32.8) 66.7 31.7-131.5
 5-17 years 62.0 (28.5) 59.4 26.6-102.1
 18-34 years 56.7 (33.3) 47.4 19.1-101.5
 35-44 years 60.3 (26.4) 59.2 22.5-103.1
 45-55 years 54.8 (25.1) 48.7 20.3-105.5

Females
 4-9 years 74.2 (26.5) 72.1 28.5-117.1
 10-14 years 67.5 (31.3) 63.5 23.9-117.0
 15-17 years 49.5 (21.0) 48.0 19.7-84.6
 18-34 years 42.2 (22.6) 41.3 9.3-88.5
 35-44 years 46.1 (24.7) 44.3 10.4-83.0
 45-55 years 51.5 (22.1) 48.2 15.9-94.2

 P-Selectin, mg/L

 Mean
 (SD) Median RI

Males
 4-9 years 150 (48) 147 97-272
 10-14 years 146 (45) 141 75-232
 5-17 years 136 (41) 139 67-204
 18-34 years 147 (39) 144 84-213
 35-44 years 141 (49) 136 78-215
 45-55 years 144 (41) 142 84-213

Females
 4-9 years 140 (37) 138 86-193
 10-14 years 134 (35) 132 91-183
 15-17 years 123 (38) 114 61-200
 18-34 years 116 (33) 117 73-179
 35-44 years 129 (32) 130 80-181
 45-55 years 118 (36) 122 46-173

 L-Selectin, mg/L

 Mean
 (SD) Median RI

Males
 4-9 years 1769 (451) 1600 1332-2706
 10-14 years 1419 (495) 1361 851-2228
 5-17 years 1364 (530) 1235 722-2382
 18-34 years 1300 (608) 1159 779-2230
 35-44 years 1086 (455) 1025 651-1769
 45-55 years 963 (253) 911 625-1468

Females
 4-9 years 1808 (562) 1747 1040-3213
 10-14 years 1410 (477) 1219 905-2410
 15-17 years 1307 (337) 1288 802-1969
 18-34 years 1262 (535) 1144 717-2147
 35-44 years 1082 (466) 985 655-1949
 45-55 years 1107 (434) 974 664-1997

(a) RI, reference interval.
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Title Annotation:Technical Briefs
Author:Ponthieux, Anne; Herbeth, Bernard; Droesch, Suzanne; Lambert, Daniel; Visvikis, Sophie
Publication:Clinical Chemistry
Date:Sep 1, 2003
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